Clinical Question

Does thrombolysis with tenecteplase reduce mortality or hemodynamic collapse in patients with sub-massive PE at 7 days compared to placebo?

Conclusion

Fibrinolytic therapy prevented hemodynamic compensation but at the risk of increased hemorrhage and stroke

Major Points

The Pulmonary Embolism Thrombolysis (PEITHO) trial evaluated a single-dose tenecteplase with heparin therapy for the treatment of “intermediate risk” acute pulmonary embolism. Intermediate risk was defined as patient with pulmonary embolism in addition to right ventricular dysfunction on imaging, and elevated cardiac biomarkers. For the primary composite endpoint of death or hemodynamic deterioration within 7 days, 2.6% of patients in the immediate thrombolysis group met the outcome vs. 5.6% of patients in the usual treatment arm (OR 0.44, p=0.02).

Intermediate risk PE has often been used synonymously with submassive PE however a standard definition has not been universally accepted. The American Heart Association has maintained that for massive pulmonary embolism, thrombolysis with tPA is an effective treatment strategy.[1]. This trial addressed thrombolysis in patients who are hemodynamically stable but had moderate PE evidenced on CTA. Commonly, the group termed, sub-massive PE includes patients with elevated troponin, BNP, or RV dysfunction on echocardiogram.. The standard of treatment for the sub-massive PE group has been unclear and thrombolysis has not been standard care for treatment, with most of these patients receiving heparin to decrease clot propagation while clot is slowly broken down[2]

Treatment with an investigational drug under another study protocol in the previous 7 days or greater, according to local requirements

Previous enrolment in this study

Known hypersensitivity to tenecteplase, alteplase, unfractionated heparin, or to any of the excipients

Pregnancy, lactation or parturition within the previous 30 days. Women of childbearing age must have a negative pregnancy test or use a medically accepted method of birth control

Known coagulation disorder (including vitamin K antagonists)

Any other condition that the investigator feels would place the patient at increased risk if the investigational therapy is initiated

Interventions

Both groups were initiated on unfractionated heparin (UFH) immediately after randomization with goal ptt 2.0-2.5x the upper limit of normal

No other anticoagulant was allowed until 48 hours after randomization

Tenecteplase Group

Tenecteplase 30-50 mg IV once over 5-10 seconds

UFH also administered

Significant between-group difference of receiving LWMH or fondaparinux before randomization

(p=0.02)

Placebo Group

Also received UFH

Outcomes

Primary Outcome

Primary outcome was all cause mortality or hemodynamic decompensation at 7 days

Tenecteplase group: 2.6%

Placebo group: 5.6%

Hemodynamic Decompensation

SBP <90 mmHg ≥ 15 min

Decrease in SBP ≥ 40 mmHg for ≥ 15min with end organ hypoperfusion or need for vasopressors

Secondary Outcomes

All-cause mortality

7 days: 1.2% vs. 1.8% (OR 0.65; 95% CI 0.23-1.85; P=0.42)

30 days: 2.4% vs. 3.2% (OR 0.73; 95% CI 0.34-1.57; P=0.42)

Subgroup analysis

Hemodynamic decompensation at 7 days

1.6% vs. 5.0% (OR 0.30; 95% CI 0.14-0.68; P=0.002; NNT 29)

Recurrent PE at 7 days

0.2% vs. 1.0% (OR 0.20; 95% CI 0.02-1.68; P=0.12; NNT 125)

Bleeding at 7 days

Minor bleeding: 32.6% vs. 8.6%

Major bleeding: 11.5% vs. 2.4%

Stroke at 7 days

2.4% vs. 0.2% (OR 12.10; 95% CI 1.57-93.39; P=0.003; NNH 45)

Ischemic: 0.4% vs. 0%

Hemorrhagic: 2.0% vs. 0.2%

Criticisms & Further Discussion

Major bleeding occurred five times as frequent in the treatment arm

Half of the deaths in the placebo arm were "sudden unexplained" or "other" compared with bleeding or stroke complications in the thrombolysis arm

Not all placebo patients developing hemodynamic collapse received subsequent thrombolysis; likewise, almost half of those who received open-label thrombolysis had no hemodynamic collapse.

Meta-analysis shows that patients with pulmonary embolism, including those who were hemodynamically stable with right ventricular dysfunction, thrombolytic therapy was associated with lower rates of all-cause mortality and increased risks of major bleeding and ICH.[5] Second, in a subset of 1331 patients older than 65 years, thrombolysis was associated with a higher rate of major bleeding (12.93% vs 4.10%)[6]

Meta-analysis of thrombolytics in PE found NNT=59 for all-cause mortality and NNH=79 for intracranial hemorrhage. Major bleeding was not significantly increased for patients age 65 or younger Odds ratio=1.25 [7]

↑Konstantinides S. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation 1997;96: 882e888